The past decade has witnessed remarkable advances in scientific knowledge and technology that will have significant impacts upon human health. With the sequencing of the human and other genomes, new genes, gene products, signaling and metabolic pathways are being discovered at a rapid pace, thereby leading to the identification of numerous potential therapeutic targets that would have otherwise been unknown. Biological assays to determine activities have led to the discovery of numerous small molecules that have promising physiochemical and physiological properties. Conversely, small molecules are increasingly serving as invaluable tools to probe biological function and mechanism. Despite the stunning progress that has been made, one significant challenge that remains lies in identifying biologically active small molecules having novel chemotypes and structures. This problem is best addressed by the chemical synthesis of new, functionalized heterocyclic frameworks that may be easily elaborated to optimize biological activity. We will thus apply chemistry we have uniquely developed for the diversity-oriented synthesis of functionalized, heterocyclic scaffolds to prepare pure (>90%) samples of collections of distinct, novel compounds for submission to the NIH Molecular Libraries Small-Molecule Repository (MLSMR). These small molecules will be derived from a series of approximately 25-30 different heterocyclic scaffolds, some of which are both structurally and functionally complex, having different substitution patterns that are explicitly designed to optimally occupy three-dimensional space of the biological target. The design of each collection of molecules is based upon a sound biological rationale. For example, many members of the proposed libraries are natural product-like, whereas others embody known privileged structures. Prior to the synthesis of each library, computational methods, including diversity mapping, will be employed to ensure maximal structural diversity in the collection. Individual members of the collections will be verified as drug-like by application of various standard metrics, including the Lipinski Rule of Five. Each molecule will bear functionality that will allow for further development of structure activity relationships. It is expected that compounds submitted to the MLSMR will exhibit biological activities in a broad range of assays and serve as useful tools to explore biological function, thereby leading to significant improvements in disease treatment.